The present invention claims the priority of Taiwan patent application serial No. 88122319, filed on Dec. 15, 1999, which is herein incorporated by reference.
The present invention relates to novel ophthalmic drug delivery formulations which comprise, without limitation, a Carbopol solution, a Pluronic solution, or a combination of Carbopol and Pluronic. This formulation is a free flowing liquid with low viscosity at non-physiological condition and undergoes in situ phase transition to form strong gel at physiological condition. The ophthalmic drug delivery formulations are especially suitable for use with ophthalmic drugs such as pilocarpine hydrochloride to treat glaucoma. The present invention also relates to the method for making the ophthalmic drug delivery formulation.
Most of the conventional ophthalmic drug delivery systems encounter great problems due to unique physiological conditions of the eye, i.e., when a conventional liquid ophthalmic formulation is applied to the eye, upon instillation, it is immediately eliminated from the precorneal area of the eye because of lacrimal secretion and nasolacrimal drainage. As a result, only 1-10% of the ophthalmic drugs can be utilized by patients and a frequent instillation of concentrated solutions is necessary in order to achieve the desired therapeutic effects.
To lengthen the retention time of instilled ophthalmic drug in the eye and to enhance the bioavailability of the ophthalmic drug, various ophthalmic vehicles have been developed. Examples of such ophthalmic vehicles include various inserts, ointments, suspension, and aqueous gels. However, these ophthalmic vehicles have their drawbacks. For example, the use of ointments often causes blurred vision. Also, insert is not particularly popular among patients due to its low patient compliance.
Among the ophthalmic vehicles, one kind, the so-called in situ gel forming systems, has been particularly useful for prolonging precorneal retention time and improving ocular bioavailability of the ophthalmic drugs. Typically, an in situ gel forming system is made of polymers. These polymers can undergo a phase transition from a solution (liquid) to a gel once they have been instilled in the cul-de-sac of the eye.
Various in situ gel forming systems have been reported. For example, Gurny et al., J. Contr. Release (1985), 2:353-361, discloses an ocular drug delivery system which includes cellulose acetophthalate (CAP) latex and Carbopol solution. Carbopol is the trademark of B.F. Goodrich Company""s carboxy vinyl polymers. Rozier et al., Int. J. Pharm. (1989), 57: 163-168, discloses an ion-activated gelling vehicle with a trademark of Gelrite(copyright). However, Rozier et al.""s gelling vehicle has the disadvantages of being converted into gel in the presence of mono- or divalent cations.
Joshi et al.""s U.S. Pat. No. 5,252,318 discloses reversibly gelling aqueous compositions which contain at least one pH-sensitive reversibly gelling polymer (such as carboxy vinyl linear or branched or cross-linked polymers of the monomers) and at least one temperature-sensitive reversibly gelling polymer (such as alkylcellulose, hydroxyalkyl cellulose, block copolymers of polyoxyethylene and polyoxypropylene, and tetrafunctional block polymers of polyoxyethylene and polyoxypropylene and ethylenediamine). Joshi et al.""s compositions exhibit significant changes in viscosity in response to substantially simultaneous changes in both temperature and pH.
Kumar et al., J. Ocular Pharmacol. (1994), 10: 47-56, discloses an ocular drug delivery system based on a combination of Carbopol and methylcellulose. The sol-gel transition of the combination occurs primarily due to an increase in pH because of the presence of Carbopol. Kumar et al., J. Pharm. Sci. (1995), 84: 344-348 (1995), discloses yet another ocular drug delivery system containing Carbopol and hydroxyproplymethylcellulose. In both systems, a viscosity-enhancing polymer is added to achieve a reduction in Carbopol concentration without compromising the in situ gelling properties as well as overall rheological behaviors.
Finkenaur et al.""s U.S. Pat. No. 5,427,778 discloses a gel formulations contains a polypeptide growth factor and a water soluble, pharmaceutically or ophthalmically compatible polymeric material for providing viscosity within various ranges determined by the application of the gel. Both Carbopol gels and Pluronic gels, respectively, are disclosed in the patent. Pluronic is the trademark for BASF""s polyoxyethylene-polyoxypropylene block copolymers.
Viegas et al.""s U.S. Pat. No. 5,593,683 discloses a method for making a thermoreversible gels for drug or diagnostic agent delivery. The gels contain a pharmaceutical agent, a surfactant, and a polyalkylene polyether. The combined total amount of the surfactant and the polyalkylene polyether does not exceed about 10% by weight.
Because most of the in situ gel forming systems described above require the use of high concentrations of polymer to form gel upon instillation in the eye, they are not suitable for use in ophthalmic drug delivery. Also, in the case of Carbopol polymer, the increase in Carbopol concentration produces an acidic environment which may in turn cause irritation to the eye tissue. Thus, finding a gelling vehicle which demonstrates good solubility and fluidity at non-physiological condition (i.e., pH 4.0 at 25xc2x0 C.), and can be converted to gel at physiological condition (i.e., pH 7.4, 37xc2x0 C.) is definitely in demand particularly in the ophthalmic drug delivery industry.
The present invention provides ophthalmic drug delivery formulations which either contain Carbopol(copyright) (hereinafter xe2x80x9cCarbopolxe2x80x9d) or Pluronic(copyright) (hereinafter xe2x80x9cPluronicxe2x80x9d) or a combination of Carbopol and Pluronic. The preferred formulation is the one containing a combination of Carbopol and Pluronic.
Carbopol is a trademark of B.F. Goodrich Company. It contains a group of carboxy vinyl polymer (or polyacrylic acid polymer). The preferred carboxy vinyl polymer is a high molecular weight (preferably MW above 1,000,000; and most favorably MW above 3,000,000) polymer, such as Carbopol 934P which has a molecular weight of about 3,000,000. The preferred Carbopol concentration is 0.3-0.4% (w/v), most favorably 0.3% (w/v).
Pluronic is a trademark of BASF""s polyoxyethylene-polyoxypropylene block copolymers. The preferred Pluronic is Pluronic F-127. The preferred concentration of Pluronic is 14% (w/v).
In the ophthalmic drug delivery formulation containing a combination of Carbopol and Pluronic, the preferred concentration of Carbopol is no more than 0.5% (w/v), most favorably 0.3%. The preferred Pluronic concentration is no more than 15% (w/v), most favorably 14% (w/v).
The ophthalmic drug delivery formulation of the present invention has the characteristics of being in free flowing state at non-physiological condition (i.e., pH 4.0 and 25xc2x0 C.) and forming gel at physiological condition (i.e., pH 7.4 and 37xc2x0 C.).
The ophthalmic drug delivery formulation of the present invention is especially suitable for use with any of the ophthalmically active drugs, particularly amine drugs known for use in the treatment of diseases of the eye, such as glaucoma. The preferred drug is pilocarpine hydrochloride.
The present invention also provides a method for preparing the ophthalmic drug delivery formulation containing a combination of Carbopol and Pluronic, which includes the following steps: (1) dispersing the Carbopol in water to form a Carbopol solution (preferably at 0.3% [w/v]); and (2) adding the preferred amount of Pluronic (preferably at 14% [w/v]) in the Carbopol solution to form said ophthalmic drug delivery formulation. Additionally, an ophthalmic drug, such as pilocarpine hydrochloride can be added to the ophthalmic drug delivery formulation.
Finally, the present invention provides a method of treating patients with eye diseases, such as glaucoma, by topically administering to the patient an effective amount of the ophthalmic drug delivery system containing 0.3% (w/v) of Carbopol and 14% (w/v) of Pluronic. The preferred ophthalmic drug is pilocarpine hydrochloride. The preferred pH of the ophthalmic drug delivery system is no more than pH 5.5.